The alarming increase in Plasmodium falciparum resistance to commonly used anti-malarial drugs represents a major public health threat. The impact is however difficult to quantify. In low transmission areas, an increase in acute manifestations ("epidemic") is often quickly apparent and resistance is rapidly propagated due to high drug pressure on existing parasite populations. In high transmission areas, the clinical effects are mainly prolonged/chronic infections with increasing risk of severe anemia. Mortality estimates from public health records in Africa generally suggest significant increases (from 2- to 11-fold) in malaria-associated mortality among children when resistance develops and spreads. Hospital attendances and admissions show similar trends. Change of policy to alternative efficacious treatment with radical cure is necessary at an earlier stage (from 10% treatment failure) than previously assumed in order to prevent deaths in millions of African children. Early switch to artemisinin based combination therapy (ACT) represents such a critical and urgent strategy.